Herpesviruses package virally-encoded transcriptional activating proteins into the tegument layer of their virions. The tegument transactivator encoded by human cytomegalovirus (HCMV) is the pp71 protein. When cells are productively infected, pp71 is released into the cytoplasm, translocates to the nucleus, and activates viral immediate early (IE) transcription. Herpesviruses also establish latent infections where productive phase gene expression is absent or attenuated. Tegument-delivered pp71 remains in the cytoplasm of the primary CD34+ cells where HCMV establishes latency. Thus, the subcellular localization of tegument-delivered pp71 differentially correlates with IE transcriptional activity during lytic infection (pp71 in the nucleus, IE transcription on) and latency (pp71 in the cytoplasm, IE transcription off). Here, we propose to identify the natural way in which the subcellular localization of tegument-delivered pp71 is controlled as a first step toward developing a method to artificially control it, and thus control the fate of an HCMV infection (lytic or latent).